Psychotropic medication in pregnancy: The cost-benefit ratio revised G.A. Alevizopoulos

Transcript

1 PSYCHIATRIKI Quarterly journal published by the Hellenic Psychiatric Association, Volume 26, No 3 July-September 2015 Psychotropic medication in pregnancy: The cost-benefit ratio revised G.A. Alevizopoulos Pharmacological agents under research for the maintenance treatment in bipolar disorder S. Dimitrakopoulos & G. Konstantakopoulos Mental health services commissioning and provision: Lessons from the UK? G. Ikkos et al NICE recommendations for psychotherapy in depression: Of limited clinical utility D. McQueen & P.St. John Smith Mental health and sexual activity according to ancient Greek physicians K. Laios et al Validity of the Greek Eating Disorder Examination Questionnaire 6.0 (EDE-Q-6.0) among Greek adolescents S. Pliatskidou et al Inter-rater reliability of the Greek version of CAARMS among two groups of mental health professionals C. Kollias et al MEDLINE/PubMed, ndex Copernicus, Google Scholar EMBASE/Excerpta Medica, GFMER, CIRRIE, SCIRUS for Scientific Inf., SCOhost TM Iatrotek GR ISSN Ôñéìçíéáßá êäïóç ôçò, 26, 3,

2 Καταχωρείται και περιλαμβάνεται στα MEDLINE/PubMed, Ιndex Copernicus, Google Scholar, EMBASE/Excerpta Medica, GFMER, CIRRIE, SCIRUS for Scientific Inf., EBSCOhost TM και στο Iatrotek ΨΥΧΙΑΤΡΙΚΗ Τριμηνιαία έκδοση της Ελληνικής Ψυχιατρικής Εταιρείας Παπαδιαμαντοπούλου 11, Αθήνα Τηλ.: , Fax: Εκδότης: Βασίλης Κονταξάκης Ιδιοκτήτης: Ελληνική Ψυχιατρική Εταιρεία Παπαδιαμαντοπούλου 11, Αθήνα Τηλ.: ΣΥΝΤΑΚΤΙΚΗ ΕΠΙΤΡΟΠΗ Επίτιμος Πρόεδρος: Γ.Ν. Χριστοδούλου Πρόεδρος: Β. Κονταξάκης Αναπληρωτής Πρόεδρος: Δ. Πλουμπίδης Μέλη: Ι. Ζέρβας, Σ. Θεοδωροπούλου, Δ. Καραΐσκος, Γ. Κωνσταντακόπουλος Μ. Μαργαρίτη Συνεργάτης: Π. Φερεντίνος M. Abou-Saleh (UK) H. Akiskal (USA) G. Alexopoulos (USA) N. Andreasen (USA) S. Bloch (Australia) Μ. Botbol (France) N. Bouras (UK) C. Höschl (Czech Rep.) Γραμματεία ΕΨΕ: Υπεύθυνη: Ε. Γκρέτσα Τηλ.: , Fax: Ιστοσελίδα: FB: EΛΛΗΝΙΚΗ ΨΥΧΙΑΤΡΙΚΗ ΕΤΑΙΡΕΙΑ Εργασίες για δημοσίευση, επιστολές, βιβλία για παρουσίαση να απευθύνονται στον Πρόεδρο της Συντακτικής Επιτροπής: Παπαδιαμαντοπούλου 11, Αθήνα Ετήσιες συνδρομές του Περιοδικού: Eσωτερικού 40,00 Eξωτερικού $ 80,00 + ταχυδρομικά Μεμονωμένα τεύχη 10,00 Καταβάλλονται με επιταγή στον ταμία της ΕΨΕ: Παπαδιαμαντοπούλου 11, Αθήνα Τα ταμειακώς εντάξει μέλη της Εταιρείας δεν υποχρεούνται σε καταβολή συνδρομής Indexed and included in MEDLINE/PubMed, Ιndex Copernicus, Google Scholar, EMBASE/Excerpta Medica, GFMER, CIRRIE, SCIRUS for Scientific Inf., EBSCOhost TM and in Iatrotek PSYCHIATRIKI Quarterly journal published by the Hellenic Psychiatric Association 11, Papadiamantopoulou str., Athens Tel.: , Fax: Publisher: Vassilis Kontaxakis editor@psych.gr Owner: Hellenic Psychiatric Association 11, Papadiamantopoulou str., Athens Tel.: EDITORIAL BOARD Emeritus Εditor: G.N. Christodoulou Editor: V. Kontaxakis Associate Εditor: D. Ploumpidis Members: I. Zervas, S. Theodoropoulou, D. Karaiskos G. Konstantakopoulos, M. Margariti Collaborator: P. Ferentinos INTERNATIONAL ADVISORY BOARD H. Ghodse (UK) D. Lecic-Tosevski (Serbia) P. Gökalp (Turkey) C. Lyketsos (USA) G. Ikkos (UK) M. Maj (Italy) A. Marneros (Germany) R.A. Kallivayalil (India) J. Mezzich (USA) M. Kastrup (Denmark) H.J. Möller (Germany) K. Kirby (Australia) R. Montenegro (Argentina) V. Krasnov (Russia) C. Pantelis (Australia) G. Papakostas (USA) G. Petrides (USA) R. Salokangas (Finland) O. Steenfeld-Foss (Norway) A. Tasman (USA) N. Tataru (Romania) P. Tyrer (UK) Secretariat: Head: H. Gretsa Tel.: (+30) , Fax: (+30) psych@psych.gr, Web-site: Manuscripts, letters, books for review should be addressed to the Editor: 11 Papadiamantopoulou str., GR Athens, Greece Annual subscriptions of the Journal: or $ postage each separate issue are payable by check to the treasurer of the Hellenic Psychiatric Association: 11, Papadiamantopoulou str., GR Athens For the members of the Association in good standing subscription is free ΕΠΙΜΕΛΕΙΑ ΕΚΔΟΣΗΣ ΕΝ ISO 9001:2000 Αδριανείου 3 και Κατεχάκη, Αθήνα (Ν. Ψυχικό) Τηλ.: , Fax: betamedarts@otenet.gr e-shop: EN ISO 9001:2000 Υπεύθυνος τυπογραφείου Α. Βασιλάκου, Αδριανείου Αθήνα Τηλ EDITING ΕΝ ISO 9001:2000 3, Adrianiou str., GR Αthens-Greece Τel.: (+30) (+30) , Fax: (+30) betamedarts@otenet.gr, e-shop: EN ISO 9001:2000 Printing supervision A. Vassilakou, 3 Adrianiou str. GR Athens Tel. (+30)

3 ΕΛΛΗΝΙΚΗ ΨΥΧΙΑΤΡΙΚΗ ΕΤΑΙΡΕΙΑ HELLENIC PSYCHIATRIC ASSOCIATION ΔΙΟΙΚΗΤΙΚΟ ΣΥΜΒΟΥΛΙΟ Πρόεδρος: Δ. Πλουμπίδης Αντιπρόεδρος: Β. Κονταξάκης Γεν. Γραμματέας: Α. Μιχοπούλου Ταμίας: Α. Ζαχαριάδης Σύμβουλοι: Λ. Μαρκάκη Β. Μποζίκας Χ. Τσόπελας ΠΕΙΘΑΡΧΙΚΟ ΣΥΜΒΟΥΛΙΟ Πρόεδρος: Ι. Πιτταράς Μέλη: Ε. Σιούτη Ε. Μαραγκουδάκη ΕΞΕΛΕΓΚΤΙΚΗ ΕΠΙΤΡΟΠΗ Μέλη: N. Τζαβάρας Φ. Μωρόγιαννης Ι. Χριστόπουλος EXECUTIVE COUNCIL Chairman: D. Ploumpidis Vice-Chairman: V. Kontaxakis Secretary General: A. Michopoulou Treasurer: A. Zachariadis Consultants: L. Markaki V. Bozikas C. Tsopelas DISCIPLINARY COUNCIL President: J. Pittaras Members: I. Siouti H. Maragoudaki FINANCIAL CONTROL COMMITTΕE Members: Ν. Tzavaras F. Morogiannis J. Christopoulos ΠΕΡΙΦΕΡΕΙΑΚΑ ΤΜΗΜΑΤΑ ΑΘΗΝΩΝ Πρόεδρος: K. Kόντης Γραμματέας: Σ. Θεοδωροπούλου Ταμίας: Η. Τζαβέλλας DIVISIONS ATHENS Chairman: Secretary: Treasurer: C. Kontis S. Theodoropoulou E. Tzavellas ΜΑΚΕΔΟΝΙΑΣ Πρόεδρος: Γραμματέας: Ταμίας: Ι. Νηματούδης Ι. Διακογιάννης Π. Φωτιάδης MACEDONIA Chairman: Secretary: Treasurer: J. Nimatoudis J. Diakoyiannis P. Fotiadis ΚΕΝΤΡΙΚΗΣ ΕΛΛΑΔΟΣ Πρόεδρος: Π. Βράνας Γραμματέας: Π. Στοφόρος Ταμίας: Α. Θωμάς CENTRAL GREECE Chairman: Secretary: Treasurer: P. Vranas P. Stoforos A. Thomas ΒΟΡΕΙΟΔΥΤΙΚΗΣ ΕΛΛΑΔΟΣ & ΔΥΤΙΚΗΣ ΣΤΕΡΕΑΣ Πρόεδρος: A. Φωτιάδου Γραμματέας: Λ. Ηλιοπούλου Ταμίας: Π. Πετρίκης NORTHWESTERN GREECE Chairman: A. Fotiadou Secretary: L. Iliopoulou Treasurer: P. Petrikis ΠΕΛΟΠΟΝΝΗΣΟΥ Πρόεδρος: Γραμματέας: Ταμίας: Φ. Γουρζής Α. Κατριβάνου Ι. Βλάχος PELOPONNESUS Chairman: Secretary: Treasurer: P. Gourzis A. Katrivanou J. Vlachos ΜΕΓΑΛΗΣ ΒΡΕΤΤΑΝΙΑΣ Πρόεδρος: Ε. Παλαζίδου Γραμματέας: K. Kασιακόγια Ταμίας: Π. Λέκκος GREAT BRITAIN Chairman: Secretary: Treasurer: H. Palazidou K. Kasiakogia P. Lekkos TOMΕΑΣ ΝΕΩΝ ΨΥΧΙΑΤΡΩΝ Πρόεδρος: Ρ. Ψαράς Γραμματείς: Α. Οικονόμου, Αθ. Κανελλόπουλος ΕΝΩΣΗ ΕΛΛΗΝΩΝ ΕΙΔΙΚΕΥΟΜΕΝΩΝ ΨΥΧΙΑΤΡΩΝ Πρόεδρος: Γ. Σαμιωτάκης Γραμματέας: X. Λιάπης Ταμίας: Β. Ηλιάδου SECTOR OF YOUNG PSYCHIATRISTS Chairman: R. Psaras Secretaries: A. Economou, Ath. Kanellopoulos ASSOCIATION OF GREEK PSYCHIATRIC TRAINEES Chairman: G. Samiotakis Secretary: C. Liapis Treasurer: V. Iliadou

4 ΚΛΑΔΟΙ ΑΥΤΟΚΑΤΑΣΤΡΟΦΙΚΩΝ ΣΥΜΠΕΡΙΦΟΡΩΝ Πρόεδρος: Μ. Χαβάκη-Κονταξάκη Γραμματείς: Δ. Παππά, Κ. Παπλός ΒΙΑΙΩΝ ΣΥΜΠΕΡΙΦΟΡΩΝ Πρόεδρος: Χ. Τσόπελας Γραμματείς: M. Δημητρακά, Π. Ντούνας ΒΙΟΛΟΓΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Π. Σακκάς Γραμματείς: Α. Μπότσης, Κ. Ψάρρος ΔΙΑΠΟΛΙΤΙΣΜΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Σ. Καπρίνης Γραμματείς: Σ. Μπουφίδης, Ε. Παρλαπάνη ΔΙΑΤΑΡΑΧΕΣ ΠΡΟΣΛΗΨΗΣ ΤΡΟΦΗΣ Πρόεδρος: Ε. Βάρσου Γραμματείς: Γ. Μιχόπουλος, Φ. Γονιδάκης ΙΔΙΩΤΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Λ. Μαρκάκη Γραμματείς: Γ. Γκιουζέλης, Γ. Πολυχρόνη ΙΣΤΟΡΙΑΣ ΤΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Δ. Πλουμπίδης Γραμματείς: Αθ. Καράβατος, Ι. Πολυχρονίδης ΚΛΙΝΙΚΗΣ ΨΥΧΟΦΑΡΜΑΚΟΛΟΓΙΑΣ Πρόεδρος: Β. Αλεβίζος Γραμματείς: X. Tουλούμης, Ειρ. Σιούτη ΚΟΙΝΩΝΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Α. Μιχοπούλου Γραμματείς: Γ. Γαρύφαλλος, Σ. Θεοδωροπούλου ΟΥΣΙΟΕΞΑΡΤΗΣΕΩΝ Πρόεδρος: Ι. Λιάππας Γραμματείς: Ι. Διακογιάννης, Θ. Παπαρρηγόπουλος ΠΑΙΔΟΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Δ. Αναστασόπουλος Γραμματείς: Δ. Αναγνωστόπουλος, Κ. Κανελλέα ΠΡΟΛΗΠΤΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Β. Κονταξάκης Γραμματείς: Δ. Κόντης, Η. Τζαβέλλας ΣEΞΟΥΑΛΙΚΟΤΗΤΑΣ ΚΑΙ ΔΙΑΠΡΟΣΩΠΙΚΩΝ ΣΧΕΣΕΩΝ Πρόεδρος: Λ. Αθανασιάδης Γραμματείς: Κ. Παπασταμάτης, Η. Μουρίκης ΣΥΜΒΟΥΛΕΥΤΙΚΗΣ - ΔΙΑΣΥΝΔΕΤΙΚΗΣ ΨΥΧΙΑΤΡΙΚΗΣ & ΨΥΧΟΣΩΜΑΤΙΚΗΣ Πρόεδρος: Θ. Υφαντής Γραμματείς: Α. Καρκανιάς, Μ. Διαλλινά TEXNΗΣ & ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Σ. Κρασανάκης Γραμματείς: Η. Βλάχος, Χ. Γιαννουλάκη ΤΗΛΕΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Κ. Κατσαδώρος Γραμματείς: Ι. Χατζιδάκης, Ι. Αποστολόπουλος ΦΙΛΟΣΟΦΙΑΣ & ΨΥΧΙΑΤΡΙΚΗΣ Πρόεδρος: Ι. Ηλιόπουλος Γραμματείς: Γ. Νικολαΐδης, A. Κομπορόζος ΨΥΧΙΑΤΡΙΚΗΣ ΗΘΙΚΗΣ & ΔΕΟΝΤΟΛΟΠΑΣ Πρόεδρος: Γ. Χριστοδούλου Γραμματείς: Ι. Γκιουζέπας, Α. Δουζένης ΨΥΧΙΑΤΡΙΚΗΣ & ΘΡΗΣΚΕΙΑΣ Πρόεδρος: Α. Αυγουστίδης Γραμματείς: Στ. Κούλης, Κ. Εμμανουηλίδης ΨΥΧΙΚΗΣ ΥΓΕΙΑΣ ΓΥΝΑΙΚΩΝ & ΨΥΧΙΑΤΡΙΚΗΣ ΤΗΣ ΑΝΑΠΑΡΑΓΩΓΗΣ Πρόεδρος: Ι. Ζέρβας Γραμματείς: Ε. Λαζαράτου, Α. Λεονάρδου ΨΥΧΙΑΤΡΟΔΙΚΑΣΤΙΚΗΣ Πρόεδρος: Γ. Τζεφεράκος Γραμματείς: Δ. Τσακλακίδου, Ι. Γιαννοπούλου ΨΥΧΟΘΕΡΑΠΕΙΑΣ Πρόεδρος: Χ. Καραμανωλάκη Γραμματείς: Κ. Χαραλαμπάκη, Γ. Μιχόπουλος ΨΥΧΟΓΗΡΙΑΤΡΙΚΗΣ Πρόεδρος: Ν. Δέγλερης Γραμματείς: Γ. Παπατριανταφύλλου, Κ. Νικολάου ΨΥΧΟΜΕΤΡΙΚΩΝ & ΝΕΥΡΟΨΥΧΟΛΟΓΙΚΩΝ ΜΕΤΡΗΣΕΩΝ Πρόεδρος: Κ. Φουντουλάκης Γραμματείς: Ι. Νηματούδης, Ι. Ζέρβας ΨΥΧΟΟΓΚΟΛΟΓΙΑΣ Πρόεδρος: Αθ. Καρκανιάς Γραμματείς: Κ. Παπλός, Μ. Συγγελάκης ΨΥΧΟΠΑΘΟΛΟΓΙΑΣ Πρόεδρος: Ν. Τζαβάρας Γραμματείς: Γ. Καπρίνης, Μ. Διαλλινά ΨΥΧΟΦΥΣΙΟΛΟΓΙΑΣ Πρόεδρος: Ι. Λιάππας Γραμματείς: Ι. Νηματούδης, Χ. Παπαγεωργίου SECTIONS SELF-DESTRUCTIVE BEHAVIORS Chairman: B. Havaki-Kontaxaki Secretaries: D. Pappa, K. Paplos VIOLENT BEHAVIORS Chairman: C. Tsopelas Secretaries: M. Dimitraka, P. Dounas BIOLOGICAL PSYCHIATRY Chairman: P. Sakkas Secretaries: A. Botsis, C. Psarros CROSS-CULTURAL PSYCHIATRY Chairman: S. Kaprinis Secretaries: S. Boufidis, H. Parlapani EATING DISORDERS Chairman: E. Varsou Secretaries: J. Michopoulos, F. Gonidakisi PRIVATE PRACTICE PSYCHIATRY Chairman: L. Markaki Secretaries: J. Giouzelis, G. Polychroni HISTORY OF PSYCHIATRY Chairman: D. Ploumpidis Secretaries: Ath. Karavatos, J. Polyhronidis PSYCHOPHARMACOLOGY Chairman: V. Alevizos Secretaries: C. Touloumis, I. Siouti SOCIAL PSYCHIATRY Chairman: Α. Michopoulou Secretaries: G. Garyfallos, S. Theodoropoulou SUBSTANCE ABUSE Chairman: J. Liappas Secretaries: J. Diakoyiannis, T. Paparrigopoulos CHILD PSYCHIATRY Chairman: D. Anastasopoulos Secretaries: D. Anagnostopoulos, K. Kanellea PREVENTIVE PSYCHIATRY Chairman: V. Kontaxakis Secretaries: D. Kontis, E. Tzavellas SEXUALITY AND INTERPERSONAL RELATIONSHIPS Chairman: L. Athanasiadis Secretaries: K. Papastamatis, H. Mourikis CONSULTATION-LIAISON PSYCHIATRY & PSYCHOSOMATICS Chairman: T. Hyphantis Secretaries: A. Karkanias, M. Diallina ART & PSYCHIATRY Chairman: S. Krasanakis Secretaries: E. Vlachos, C. Giannoulaki TELEPSYCHIATRY Chairman: K. Katsadoros Secretaries: J. Chatzidakis, J. Apostolopoulos PHILOSOPHY & PSYCHIATRY Chairman: J. Iliopoulos Secretaries: G. Nikolaidis, Α. Komborozos PSYCHIATRY & ETHICS Chairman: G. Christodoulou Secretaries: J. Giouzepas, A. Douzenis PSYCHIATRY & RELIGION Chairman: A. Avgoustidis Secretaries: S. Koulis, K. Emmanouilidis WOMEN'S MENTAL HEALTH & REPRODUCTIVE PSYCHIATRY Chairman: J. Zervas Secretaries: H. Lazaratou, A. Leonardou FORENSIC PSYCHIATRY Chairman: G. Tzeferakos Secretaries: D. Tsaklakidou, J. Giannopoulou PSYCHOTHERAPY Chairman: C. Karamanolaki Secretaries: Κ. Charalambaki, J. Michopoulos PSYCHOGERIATRICS Chairman: N. Degleris Secretaries: J. Papatriantafyllou, K. Nikolaou PSYCHOMETRIC & NEUROPSYCHOLOGIC MEASUREMENTS Chairman: K. Fountoulakis Secretaries: J. Nimatoudis, J. Zervas PSYCHO-ONCOLOGY Chairman: A. Karkanias Secretaries: K. Paplos, M. Syngelakis PSYCHOPATHOLOGY Chairman: N. Tzavaras Secretaries: G. Kaprinis, M. Diallina PSYCHOPHYSIOLOGY Chairman: J. Liappas Secretaries: J. Nimatoudis, C. Papageorgiou

5 PSYCHIATRIKI Quarterly journal published by the Hellenic Psychiatric Association CONTENTS Editorial Psychotropic medication in pregnancy: The cost-benefit ratio revised G.A. Alevizopoulos Review Pharmacological agents under research for the maintenance treatment in bipolar disorder S. Dimitrakopoulos & G. Konstantakopoulos Special articles Mental health services commissioning and provision: Lessons from the UK? G. Ikkos, Ph. Sugarman, N. Bouras NICE recommendations for psychotherapy in depression: Of limited clinical utility D. McQueen & P.St. John Smith Mental health and sexual activity according to ancient Greek physicians K. Laios, G. Tsoucalas, Μ.-Ι. Kontaxaki, M. Karamanou, M. Sgantzos, G. Androutsos Research article Validity of the Greek Eating Disorder Examination Questionnaire 6.0 (EDE-Q-6.0) among Greek adolescents S. Pliatskidou, M. Samakouri, E. Kalamara, E. Papageorgiou, K. Koutrouvi, C. Goulemtzakis, E. Nikolaou, M. Livaditis Brief communication article Inter-rater reliability of the Greek version of CAARMS among two groups of mental health professionals C. Kollias, V. Kontaxakis, B. Havaki-Kontaxaki, M.B. Simmons, N. Stefanis, C. Papageorgiou Obituary Future scientific meetings

6 ΨΥΧΙΑΤΡΙΚΗ Τριμηνιαία έκδοση της Ελληνικής Ψυχιατρικής Εταιρείας ΠΕΡΙΕΧΟΜΕΝΑ Άρθρο σύνταξης Φάρμακα και κύηση: Αναθεωρώντας το ισοζύγιο οφέλους-κόστους Γ.Α. Αλεβιζόπουλος Aνασκόπηση Φαρμακολογικοί παράγοντες υπό μελέτη για τη θεραπεία συντήρησης στη διπολική διαταραχή Σ. Δημητρακόπουλος & Γ. Κωνσταντακόπουλος Ειδικά άρθρα Ανάθεση και παροχή υπηρεσιών υγείας: Διδάγματα από το Ηνωμένο Βασίλειο (UK); G. Ikkos, Ph. Sugarman, N. Bouras Συστάσεις από το NICE για την ψυχοθεραπεία της κατάθλιψης: Περιορισμένη κλινική χρησιμότητα D. McQueen & P.St. John Smith Ψυχική υγεία και σεξουαλική δραστηριότητα σύμφωνα με τους αρχαίους Έλληνες ιατρούς Κ. Λάιος, Γ. Τσουκαλάς, Μ.-Ε. Κονταξάκη, Μ. Καραμάνου, Μ. Σγκάντζος, Γ. Ανδρούτσος Eρευνητική εργασία Εγκυρότητα της Eλληνικής εκδοχής του Eating Disorder Examination Questionnaire 6.0 (EDE-Q-6.0) σε δείγμα Ελλήνων εφήβων μαθητών Σ. Πλιατσκίδου, M. Σαμακουρή, E. Kαλαμαρά, E. Παπαγεωργίου, K. Kουτρουβή, Χ. Γουλεμτζάκης, E. Νικολάου, M. Λειβαδίτης Σύντομο άρθρο Η αξιοπιστία μεταξύ εκτιμητών της Ελληνικής μετάφρασης της CAARΜS σε δύο ομάδες επαγγελματιών ψυχικής υγείας Κ. Κόλλιας, Β. Κονταξάκης, Μ. Χαβάκη-Κονταξάκη, M.B. Simmons, Ν. Στεφανής, Χ. Παπαγεωργίου Nεκρολογία Προσεχείς επιστημονικές εκδηλώσεις

7 PSYCHIATRIKI 26 (3), Editorial Άρθρο σύνταξης Psychotropic medication in pregnancy: The cost-benefit ratio revised Psychiatriki 2015, 26: The use of drugs during pregnancy and breast-feeding is a long-lasting debate among scientists. Many of them support the view that the risks are minimal, since the anomalies in fetuses due to chemical compounds are approximately 1%, 1 while others argue that the effects of drug delivery in this special period of life has largely unknown delayed consequences. 2 In clinical practice the dilemma is to prescribe or not to prescribe a drug during pregnancy. Recent scientific data indicate direct adverse effects due to the state of the mental health of the mother to the fetus and, possibly, an increased risk of developing serious mental disorders in children whose mothers did not receive medication during pregnancy. 3 Given the uncertainty of the data, the optimal way of managing the problem is to educate the clinicians regarding available research data, to develop an individualized risk-benefit analysis, and finally to inform the mother and, where feasible, the father. Currently, the choice is based on a five category classification A, B, C, D and X. Regulatory authorities such as the EMA, FDA, etc. have established the five categories to indicate the potential of a drug to cause birth defects if used during pregnancy. The categories are determined by the reliability of documentation and the risk to benefit ratio. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. An extra category N has been adopted where there are no data available. In reality this classification has certain limitations. For example we have two antipsychotic drugs. The first drug is classified as B and the second one as C. How certain is that the first is safest than the second one? The answer is we don t really know. A drug with studies in animals and reports in humans can be classified in category C, while another drug just because it has limited studies or use, which did not show relevant problems, can be classified in category B and then after data accumulation can be re-classified as C or D. In general, summarized data for all the categories of the psychotropics do not show significant teratogenic effects. There are cautions for tricyclic antidepressants, some anticonvulsant and lithium (until completion of the organogenesis of the heart). 4,5 The administration of psychotropic drugs during breast-feeding is clearly more restrictive, due to the potential toxicity in the newborn and the infant, and the existence of the safer alternative of the human-like milk. Furthermore, a drug is rarely falls within the exclusion category (x) without figures to support this restriction. In practice a lot of information is collected from the traditional pregnancy registries, i.e. prospect observational studies, which monitor pregnant women from the time of entry in the registry until a short time after birth and detect major teratogenic incidents. These registries have significant limitations, such as small samples, inability to control the population, and limited followup. The presence of confounders such as tobacco use, alcohol consumption, and folic acid prescription during pregnancy can complicate the interpretation of the results. The traditional classification of the five categories is simplistic and often confuses over the complexity and ambiguity of the final choice. The limitations have led to the development of alternative methods for the assessment of the risk of medication use in pregnant women. The broader cooperation of regulatory authorities worldwide is fundamental. Since December 2014, FDA published the New Pregnancy and Lactation Labelling Rule (PLLR), 6 which has already been implemented for all new drugs by June 30, 2015, and gradually retroactively for drugs that have been licensed from 2001 and beyond. The new classification is based, like the previous one, in the traditional pregnancy registries, but also in the design of larger cohort studies, databases

8 166 PSYCHIATRIKI 26 (3), 2015 of civil claims of persons who have suffered damage, and the wider cooperation of the parties involved (regulatory agencies, scientists, users etc.). Finally this new PLLR forms a new parameter, which relates to the effect of drugs on the females and males reproductive potential. The landscape in the use of drugs in pregnancy is significantly altered after the accumulation of research. Data show that the risks from the use of drugs in pregnancy and lactation are probably overestimated, while the various diseases and conditions may have multiple adverse effects both on mothers and children. 3,7 The administration of any psychotropic drug during pregnancy is based on an integrated risk assessment plan. Parents are required to have an active role in the final decision, helped by a clear and comprehensive cost-benefit analysis from their physicians. Giorgos A. Alevizopoulos Professor in Psychiatry and Psychopharmacology Department of Psychiatry, Agioi Anargyroi Hospital, University of Athens, Αthens, Greece References 1. Brent, RL. Addressing Environmentally Caused Human Birth Defects. Pediatrics Rev 2001, 22: Snijder C, Roeleveld, N, te Velde E, Steegers E, Raat H, Hofman A et al. Occupational exposure to chemicals and fetal growth: the Generation R Study. Hum Reprod 2012, 27: Sørensen MJ, Grønborg TK, Christensen J, Parner ET, Vestergaard M, Schendel D et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol 2013, 15: Einarson A. Risks/Safety of psychotropic medication use in pregnancy. Can J Clin Pharmacol 2009, 16: Mitchell AA. Systematic identification of drugs that cause birth defects - a new opportunity. N Engl J Med 2003, 349: New Pregnancy and Lactation Labelling Rule, PLLR. Available from URL: content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements 7. Vigod SN, Gomes T, Wilton AS, Taylor VH, Ray JG. Antipsychotic drug use in pregnancy: high dimensional, propensity matched, population based cohort study. BMJ 2015, 350:h2298. doi: /bmj.h2298

9 PSYCHIATRIKI 26 (3), Άρθρο σύνταξης Εditorial Φάρμακα και κύηση: Αναθεωρώντας το ισοζύγιο οφέλους-κόστους Ψυχιατρική 2015, 26: Η χρήση φαρμάκων κατά την κύηση και τον θηλασμό έχει αποτελέσει από μακρού θέμα αντιπαράθεσης μεταξύ των επιστημόνων. Πολλοί υποστηρίζουν την άποψη ότι οι κίνδυνοι είναι ελάχιστοι, αφού μόλις το 1% των ανωμαλιών στα έμβρυα οφείλονται σε χημικούς παράγοντες, 1 ενώ αντίθετα άλλοι υποστηρίζουν ότι οι επιπτώσεις της χορήγησης φαρμάκων σε αυτή την ιδιαίτερη περίοδο της ζωής έχει, εν πολλοίς, άγνωστες μακροχρόνιες συνέπειες. 2 Στην κλινική πράξη το δίλημμα είναι να συνταγογραφήσει ή να μη συνταγογραφήσει κάποιος φάρμακα κατά την κύηση. Τα πρόσφατα ερευνητικά στοιχεία δείχνουν άμεσες δυσμενείς επιπτώσεις της κατάστασης της ψυχικής υγείας της μητέρας στο έμβρυο, και ενδεχομένως αυξημένη πιθανότητα ανάπτυξης μειζόνων διαταραχών σε παιδιά των οποίων οι μητέρες δεν έλαβαν φαρμακευτική αγωγή κατά την κύηση. 3 Με δεδομένη την αβεβαιότητα των στοιχείων, η ασφαλέστερη μέθοδος διαχείρισης του προβλήματος είναι η εκπαίδευση των κλινικών ως προς τα ερευνητικά δεδομένα, η ανάπτυξη εξατομικευμένης ανάλυσης κινδύνου-οφέλους, και τέλος η ενημέρωση της μητέρας αλλά και όπου αυτό είναι εφικτό του πατέρα. Η επιλογή μέχρι σήμερα βασίζεται στις πέντε κατηγορίες A,B,C,D και Χ χαρακτηρισμού της επικινδυνότητας χρήσης ενός φαρμάκου κατά την κύηση, οι οποίες έχουν θεσπισθεί από τις διάφορες ρυθμιστικές αρχές, όπως η EMA, FDA κ.ά. και αναφέρονται στα δεδομένα ασφαλείας κάθε φαρμακευτικού προϊόντος για ανθρώπινη χρήση. Οι κατηγορίες αυτές αντανακλούν θεωρητικά τη σχετική επικινδυνότητα ενός φαρμάκου με αύξουσα σειρά. Μια ακόμη κατηγορία Ν έχει υιοθετηθεί όταν δεν υπάρχουν διαθέσιμα δεδομένα. Η πραγματικότητα όμως είναι ότι η κατηγοριοποίηση αυτή έχει εξαιρετικά σημαντικούς περιορισμούς. Για παράδειγμα αν έχουμε ένα αντιψυχωτικό φάρμακο κατηγορίας Β και ένα κατηγορίας C, πόσο βέβαιο είναι ότι το πρώτο είναι ασφαλέστερο του δεύτερου; Η απάντηση είναι ότι δεν γνωρίζουμε. Το πρώτο φάρμακο για το οποίο έχουν γίνει μελέτες σε πειραματόζωα και υπάρχουν αναφορές από ανθρώπους, έχει ταξινομηθεί στην κατηγορία C, ενώ το δεύτερο, επειδή απλώς έχει περιορισμένες μελέτες οι οποίες δεν έδειξαν προβλήματα, στην κατηγορία Β, και στη συνέχεια μετά από σώρευση στοιχείων είναι δυνατόν να ταξινομηθεί ως C ή D. Από τις κατηγορίες των ψυχιατρικών φαρμάκων περιληπτικά τα στοιχεία δείχνουν ότι δεν εμφανίζουν ουσιώδη κίνδυνο τερατογένεσης. Επιφυλάξεις υπάρχουν για τα τρικυκλικά αντικαταθλιπτικά, κάποια αντιεπιληπτικά και το λίθιο (μέχρι την ολοκλήρωση της οργανογένεσης της καρδιάς). 4,5 Η χορήγηση ψυχοτρόπων φαρμάκων κατά τον θηλασμό είναι σαφώς πιο περιοριστική, αφενός λόγω πιθανότητας τοξικότητας στο νεογνό και το βρέφος, αφετέρου λόγω της δυνατότητας χορήγησης ασφαλούς εξανθρωποποιημένου γάλακτος. Από την άλλη πλευρά, δεν είναι σπάνιο το φαινόμενο ένα φάρμακο να εντάσσεται στην κατηγορία αποκλεισμού (Χ) χωρίς τα στοιχεία να υποστηρίζουν αυτόν τον αποκλεισμό. Στην πράξη πολλές πληροφορίες συλλέγονται από τα μητρώα κυήσεων, δηλαδή από προοπτικές μελέτες παρατήρησης, οι οποίες παρακολουθούν τις εγκύους από τον χρόνο εισαγωγής στο μητρώο μέχρι ένα μικρό διάστημα μετά τον τοκετό και ανιχνεύουν μείζονα περιστατικά τερατογένεσης. Όμως ακόμη και τα μητρώα έχουν σημαντικούς περιορισμούς, όπως περιορισμένο δείγμα, αδυναμία ελέγχου του πληθυσμού και εξαιρετικά περιορισμένη παρακολούθηση σε βάθος χρόνου. Επίσης αυτές οι μελέτες περιπλέκονται από την παρουσία συγχυτικών παραγόντων, όπως το κάπνισμα, η κατανάλωση οινοπνεύματος, αλλά και η χρήση φυλλικού οξέος κατά την κύηση. Η κλασική ταξινόμηση των πέντε κατηγοριών, η οποία είναι υπεραπλουστευμένη και συχνά συγχυτική έναντι της περιπλοκότητας και της ασάφειας της τελικής επιλογής, έχει οδηγήσει στην εξεύρεση εναλλακτικών μεθόδων εκτίμησης των κινδύνων χορήγησης φαρμάκων κατά την κύηση. Η ευρύτερη συνεργασία των ρυθμιστικών αρχών παγκοσμίως είναι αναγκαία. Ήδη από τον

10 168 PSYCHIATRIKI 26 (3), 2015 Δεκέμβριο του 2014, ο FDA δημοσιοποίησε την εφαρμογή της νέας οδηγίας ταξινόμησης φαρμάκων κατά την κύηση και τον θηλασμό (New Pregnancy and Lactation Labelling Rule, PLLR), 6 η οποία τέθηκε σε εφαρμογή για όλα τα νέα φάρμακα από 30 Ιουνίου 2015, και σταδιακά για φάρμακα που αδειοδοτήθηκαν από το 2001 και εντεύθεν με αναδρομική ισχύ. Η νέα αυτή ταξινόμηση βασίζεται, όπως και οι προηγούμενες, στα παραδοσιακά μητρώα κυήσεων, αλλά και στον σχεδιασμό μεγαλύτερων μελετών κοόρτης, των βάσεων δεδομένων από τις αστικές διεκδικήσεις ατόμων τα οποία υπέστησαν βλάβη, και στην ευρύτερη συνεργασία των εμπλεκόμενων μερών (ρυθμιστικών οργανισμών, επιστημόνων, χρηστών κ.ο.κ.). Τέλος στη νέα αυτή οδηγία εντάσσεται και μια νέα παράμετρος, η οποία αφορά στην επίδραση των φαρμάκων στο αναπαραγωγικό δυναμικό γυναικών και ανδρών. Το τοπίο στη χρήση φαρμάκων στην κύηση αλλάζει σημαντικά, μετά από τη συσσώρευση των ερευνητικών στοιχείων που δείχνουν ότι οι κίνδυνοι από τη χρήση φαρμάκων στην κύηση αλλά και στη γαλουχία έχουν μάλλον υπερτιμηθεί, ενώ παράλληλα οι διάφορες νόσοι αλλά και νοσογόνες καταστάσεις είναι δυνατόν να έχουν πολλαπλάσιες δυσμενείς επιπτώσεις τόσο στις μητέρες όσο και στα παιδιά τους. 3,7 Η σύγχρονη θεραπευτική κατά τη διάρκεια της κύησης βασίζεται σε μια ολοκληρωμένη εκτίμηση κινδύνου. Οι γονείς απαιτείται να έχουν ενεργό ρόλο στην τελική απόφαση, βοηθούμενοι από σαφείς και κατανοητές πληροφορίες εκτίμησης οφέλους-κόστους από τους θεράποντες ιατρούς τους. Γιώργος Α. Αλεβιζόπουλος Καθηγητής Ψυχιατρικής & Ψυχοφαρμακολογίας, Πανεπιστημιακή Ψυχιατρική Κλινική, ΓΟΝΚ «Οι Άγιοι Ανάργυροι» Πανεπιστήμιο Αθηνών, Aθήνα Bιβλιογραφία 1. Brent, RL. Addressing Environmentally Caused Human Birth Defects. Pediatrics Rev 2001, 22: Snijder C, Roeleveld, N, te Velde E, Steegers E, Raat H, Hofman A et al. Occupational exposure to chemicals and fetal growth: the Generation R Study. Hum Reprod 2012, 27: Sørensen MJ, Grønborg TK, Christensen J, Parner ET, Vestergaard M, Schendel D et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol 2013, 15: Einarson A. Risks/Safety of psychotropic medication use in pregnancy. Can J Clin Pharmacol 2009, 16: Mitchell AA. Systematic identification of drugs that cause birth defects - a new opportunity. N Engl J Med 2003, 349: New Pregnancy and Lactation Labelling Rule, PLLR. Available from URL: content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements 7. Vigod SN, Gomes T, Wilton AS, Taylor VH, Ray JG. Antipsychotic drug use in pregnancy: high dimensional, propensity matched, population based cohort study. BMJ 2015, 350:h2298. doi: /bmj.h2298

11 PSYCHIATRIKI 26 (3), Review Ανασκόπηση Pharmacological agents under research for the maintenance treatment in bipolar disorder S. Dimitrakopoulos, 1 G. Konstantakopoulos 1,2 1 First Department of Psychiatry, Medical School, Athens University, Eginition Hospital, Athens, Greece, 2 Section of Cognitive Neuropsychiatry, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King s College London, UK Psychiatriki 2015, 26: The treatment of bipolar disorder is a current challenge for clinicians and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance. Particularly, relapse prevention and longterm stabilization is a major therapeutic target. Combination treatment and polypharmacy are the most common choices concerning relapse prevention. Furthermore, during maintenance phase patients often experience residual mood symptoms, cognitive deficits and functional decline, which altogether illustrate the inadequate effectiveness of existing treatments and the need for new, targeted, effective and safe treatments for bipolar disorder. This review focuses on active agents for maintenance treatment in bipolar disorder investigated during the last 5 years. The compounds under investigation have been tried or tested either as monotherapy or as an add-on treatment in clinical trials that have progressed up to phase 3 or in preclinical models of bipolar disorder. While awaiting the completion of many ongoing studies, the results so far indicate that paliperidone and pregabalin may have a position in the maintenance treatment of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA antagonist, may be an interesting compound for further study. However, results on memantine, another NMDA antagonist, were not encouraging. The effects of omega-3 fatty acids and cytidine were not superior to placebo, although they both have neurotrophic and neuroprotective properties. Eslicarbazepine, which has antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding preclinical studies in experimental models, the pharmacological agents under investigation seem to follow the neurobiological pathways related to mechanism of action of lithium, which is still the "golden standard" for preventing recurrence in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-3) and the path of phosphoinositol (IMP), both probably involved in the action of lithium. Furthermore, the

12 170 S. DIMITRAKOPOULOS and G. KONSTANTAKOPOULOS PSYCHIATRIKI 26 (3), 2015 role of circadian rhythms maintenance is being studied in preclinical and clinical trials investigating the efficacy and safety of compounds CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents based on epigenetic changes and gene expression modulation, as the inhibitor of histone deacetylase (HDAC). Of note, the development of valid and reliable experimental models for bipolar disorder, which currently remains quite controversial, will contribute to the understanding of the pathogenic mechanisms and the development of new effective treatments. Improving methodology aspects of clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender differences and comorbidities, may promote research. Current studies seem promising for the development of novel pharmacological agents in the near future, although there are methodological limitations in the search for the maintenance treatment in bipolar disorder. New therapeutic targets include not only the already known mechanisms of action, but also novel pathophysiological pathways, probably implicated in bipolar disorder. Key words: Bipolar disorder, maintenance treatment, novel therapeutic targets, new pharmaceutical agents. Introduction Bipolar disorder (BD) is a chronic disease with potentially serious negative impact on patients functioning and characterized by recurrent episodes of mania or hypomania (BD I and II type respectively) and depression. Difficulties and clinical embarrassment regarding its treatment arise from the very nature of the disease chronic and recurrent and other clinical characteristics, such as heterogeneity and frequent comorbidity with other mental disorders (personality disorders, substance abuse, anxiety disorders). 1 BD treatment is a challenge for modern clinician and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of BD, i.e., antimanic, antidepressive and maintenance treatment. Especially, relapse prevention and long-term stability is a major therapeutic goal as in many cases the disorder is resistant to all first line mood-stabilizing drugs available. Augmentation strategies and polypharmacy are the most common choices for relapse prevention, 2 although it is postulated that polypharmacy does not significantly improve prognosis concerning symptom chronicity and functional impairment. 3 Moreover, patients under maintenance therapy that do not exhibit mood episode, often suffer from residual mood symptoms, 4 cognitive decline 5 and poor psychosocial functioning. 6 All the above mentioned problems concerning BD treatment demonstrate the insufficient effectiveness of existing treatments at least for a large proportion of patients and the need for new, targeted, effective and safe treatments that will enrich the pharmaceutical armamentarium for the complete remission of symptoms and better stabilization of BD patients. This review studied all pharmaceutical agents that have been tested, both in a clinical and a preclinical level, as potential effective maintenance treatment options. Material and method This review focuses on new pharmacological agents tested as BD maintenance treatment, from experimental models until phase 3 clinical trials during the last 5 years, i.e. from 2010 till April The identification of preclinical and clinical studies was conducted using databases of NIH (National Institutes of Health; EMA (European Medicines Agency; clinicaltrialsregister.eu/ctr-search/search) and WHO (World Health Organization International Clinical Registry Platform; Moreover, articles from PubMed and PLOS ONE were taken into account in order to identify relevant preclinical studies and open trials. Concerning selection

13 PSYCHIATRIKI 26 (3), 2015 PHARMACOLOGICAL AGENTS UNDER RESEARCH IN BIPOLAR DISORDER 171 criteria, compounds or pharmacological agents tested in children, adolescents or the elderly (>65 years) with BD were excluded from our study. Likewise, studies that focused exclusively on the treatment of bipolar depression, manic episode or cognitive deficits or comorbidity in BD patients, were not included. Active compounds that had progressed to phase 4 were not included in this review. The clinical trials included in this review were either completed or ongoing or were recently (from 2014 onwards) terminated for financial reasons, though they might seem promising. Pharmacological agents were further determined based on the current study phase, the type of expected therapeutic approach (monotherapy or adjunctive treatment), their mechanism of action and existing results. Regarding preclinical trials, given the lack of reliable experimental animal model for BD, only those who reported efficacy in both models of mania and depression were included in this review. Clinical trials for maintenance treatment in BD Our search revealed 9 completed studies (with or without announced results) and 9 ongoing studies for a total of 15 pharmacological agents tested from phase 1 to 3. Completed studies Seven out of 9 completed studies had reported results, 3 with favorable clinical efficacy and one with positive results for tolerability and safety, one with some evidence for efficacy, 2 did not show any significant effect, while for the remaining 2 results had not been announced at the time of writing this report (table 1). Dextromethorphan Dextromethorphan is widely used as a cough suppressant, but has been reported to have neuroprotective effects on dopaminergic neurons and anti-inflammation properties associated with neuronal degeneration in both experimental models and clinical trials. 7,8 In addition, as it shares pharmacodynamic properties similar to ketamine, 9 mainly as a NMDA-receptor antagonist and σ1 and σ2 opioid-receptor agonist, its possible use as antidepressant is under investigation. 9 In a recent phase 3 trial, dextromethorphan was studied for 12 weeks as an adjunctive treatment (30 mg and 60 mg) to 309 BD patients who had been receiving valproate, while 123 healthy subjects were used as controls (receiving valproate and placebo). 10 The study showed good efficacy for those taking dextromethorphan as an add-on treatment in terms of measuring YMRS (Young Mania Rating Scale) and HDRS (Hamilton Depression Rating Scale). 10 This finding encourages further research into the potential therapeutic role of dextromethorphan in maintenance treatment of BD. Pregabalin The use of pregabalin as an antiepileptic drug and in the treatment of generalized anxiety disorder and neuropathic pain is known. Pregabalin s chemical structure is considered to be analogous to GABA and binds with the a-2δ subunit of the voltage-dependent calcium channel. The possible use of pregabalin as an add-on treatment was addressed in an open label study 11 in 58 refractory BD patients. In 41% of patients (acute responders) that were administered an average dose of 72±69 mg/d, significant improvement was noticed in CGI scale (Clinical Global Impression) after two months. In these patients pregabalin demonstrated either antidepressant (29%), or antimanic (21%) or stabilizing properties (50%), while 42% continued to receive it after 3 years. 11 These results indicate that pregabalin might have a role in maintenance therapy. Paliperidone Paliperidone belongs to the class of atypical antipsychotics, acting primarily as a dopamine and serotonin receptor antagonist, indicated for the treatment of schizophrenia and schizoaffective disorder. In one study, 12 bipolar patients (n=152), who had recently achieved remission taking paliperidone ER (extended release), were compared to patients treated with placebo after the recession (n=148) in the maintenance phase. The results of this study at 41 months follow-up assessment con-

14 172 S. DIMITRAKOPOULOS and G. KONSTANTAKOPOULOS PSYCHIATRIKI 26 (3), 2015 Table 1. Completed studies of pharmacological agents under research for maintenance treatment in bipolar disorder. Pharmacological agent/compound Study identifier Phase Treatment as Main mechanism of action Results Dextromethorphan NCT Phase 3 Add-on Antagonism of NMDA receptors, agonism of σ1 and σ2 opioid receptors Pregabalin Open Label Phase 2 Add-on Binds to the a-2-delta subunit of voltage-dependent calcium channel Paliperidone NCT Phase 3 Monotherapy Antagonism of dopamine and serotonin receptors Eslicarbazepine NCT Phase 2 Monotherapy Blockade of voltagegated sodium channels Memantine NCT Phase 2 3 Add-on Antagonism of NMDA receptors Cytidine and omega 3 fatty acids NCT Phase 2 Add-on Neurotrophic/ neuroprotective action Cariprazine NCT Phase 3 Monotherapy Partial agonism of D2, D3 receptors Taurine NCT Phase 2 Add-on Antioxidant activity, cell membrane stabilization, calcium signalling modulation Antibodies to digoxin NCT Phase 2 Add-on Action against endogenous digitalislike compounds Significant improvement compared to placebo in YMRS and HDRS Improvement in CGI-BP scale Significant improvement compared to placebo for prevention of manic but not depressive episodes No significant differences in CGI-BP or relapse prevention. Evidence of efficacy in stabilizing after manic episode No significant differences compared to placebo in YMRS and HDRS Not superior to placebo Efficacy in safety and tolerability No results available No results available CGI-BP: Clinical Global Impression Bipolar Version; YMRS: Young Mania Rating Scale; HDRS: Hamilton Depression Rating Scale cerning relapse for any major mood episode (depressive or manic) showed that the average time to relapse in subjects who received paliperidone was 558 days compared to 283 days for those receiving placebo. However, this finding was statistically significant regarding the prevention of manic but not depressive episodes. 12 Eslicarbazepine Eslicarbazepine, chemically similar to oxcarbazepine, is used in the treatment of partial seizures by blocking voltage-gated sodium channels. Its possible role as a mood stabilizer was recently examined in a phase 2 study in 85 BD patients who had

15 PSYCHIATRIKI 26 (3), 2015 PHARMACOLOGICAL AGENTS UNDER RESEARCH IN BIPOLAR DISORDER 173 recently achieved remission after manic episode. Patients were randomized into three groups receiving eslicarbazepine as monotherapy at doses of 300 mg, 900 mg and 1800 mg respectively, and were assessed for six months. The results of this study did not show statistically significant efficacy for any of the three groups in terms of clinical improvement (as measured by the Clinical Global impression scale) or relapse prevention (as measured by the number of subjects who developed manic or depressive episode). However, secondary efficacy measurements showed that eslicarbazepine in a dosage of 300 mg to 900 mg was significantly more effective than placebo in achieving normothymia after manic episode. Eslicarbazepine was also found generally safe and well tolerated. 13 Memantine Memantine is indicated for the treatment of moderate to severe Alzheimer's disease, by acting as an NMDA-receptor antagonist. Although there is some data indicating a possible synergic role of memantine as mood stabilizer, possibly in the context of neuroprotection/neurogenesis, 14 as both antidepressant 15 and antimanic 16 agent, there has been no strong evidence in favor of these hypothetically therapeutic actions. In a 12 week, phase 2 3, double-blind study, memantine was compared to placebo as an add-on treatment in patients taking valproate without any significant difference in terms of efficacy. 17 However, studies of memantine continue to be conducted with the expectation of more favorable results. 18 Cytidine and omega 3 fatty acids Cytidine and omega 3 fatty acids as natural dietary supplements have neurotrophic and neuroprotective action. Their role in BD is not clear, with ambiguous evidence concerning efficacy In a four month, double-blind study, groups of BD patients receiving as an add-on treatment: (a) omega 3 fatty acids and (b) omega 3 fatty acids and cytidine were compared with a group receiving placebo in terms of relapse prevention. Among the compared groups no difference was noticed either in preventing relapse or improving symptoms as measured by scales of mania and depression. 22 Cariprazine Cariprazine is a new atypical antipsychotic with a novel pharmacological profile, acting as a D2, D3 receptor partial agonist. Studies have shown good tolerability and safety but also effectiveness in the treatment of manic, mixed episode, 23,24 while there are positive indications for bipolar depression. 25 A two week, phase 3 study in 402 BD patients was conducted in terms of examining safety and tolerance. This study showed promising results for its administration in longer term, as main side effect was akathisia (32.6%), but this resulted in discontinuation in only 4.7% of people who presented it. 26 Taurine Taurine is an amino-acid found in the human brain, showing antioxidant activity with a possible role in cell membrane stabilization and calcium signaling modulation. It potentially presents antidepressant activity, as shown by testing in experimental models, 27 and antiepileptic properties. 28 Its possible place in BD maintenance treatment is investigated in a phase 2 trial, but no results have yet been reported. Specific digoxin antibodies (FAB) As endogenous digitalis-like central nervous system compounds are involved in the pathogenesis of mood disorders, 29 a phase 2 trial has examined the safety and efficacy profile of specific digoxin antibodies (FAB) in BD patients, without any announced outcome measures as yet. Ongoing clinical trials for maintenance treatment in BD Our search revealed 9 clinical ongoing trials, recruiting or active (not recruiting - analysis phase) investigating 6 pharmacological agents (table 2) that had not announced results at the time of writing this report. Inositol Hexaphosphate (IP6) IP6 is involved in the intracellular system of second messenger phosphatidylinositol, with potential antidepressant role in bipolar depression, as small studies indicate. 30 In an ongoing phase 1 trial, IP6 will be

16 174 S. DIMITRAKOPOULOS and G. KONSTANTAKOPOULOS PSYCHIATRIKI 26 (3), 2015 Table 2. Ongoing clinical trials for maintenance treatment in bipolar disorder. Pharmacological agent/compound Study identifier Phase Treatment as Main mechanism of action Results (to be announced) Inositol Hexaphosphate (IP6) ELND005 (Scyllo-Inositol) NCT Phase 1 Add-on Neuroprotective action NCT Phase 2 Add-on Blockade of Amyloid-beta (Aβ) development Ramelteon NCT Phase 3 Add-on Agonist of MT1 and MT2 receptors Lurasidone NCT NCT NCT Phase 3 Add-on Monotherapy Antagonism of dopamine, serotonin and noradrenalin receptors Asenapine NCT Phase 3 Monotherapy Antagonism of D2, 5-HT 2 A receptors Aripiprazole NCT NCT Phase 3 Monotherapy Partial agonist of D2, 5-HT 2 A receptors November 2015 Recently terminated Recently terminated April 2015 July 2015 September 2017 June 2015 April 2017 February 2016 studied for safety and effectiveness as an adjunctive treatment to lithium and will be compared with lamotrigine regarding their antidepressant and stabilizing properties. ELND005 (Scyllo - Inositol) ELND005 is an experimental compound for Alzheimer's disease treatment as it appears to act as an amyloid-β aggregation inhibitor. A doubleblind phase 2 clinical trial for ELND005 as an add-on treatment in BD maintenance therapy was recently stopped by the sponsoring company for financial reasons. Ramelteon Ramelteon binds to melatonergic receptors MT1 and MT2 and beyond its use as hypnotic, it can play a role in the regulation of circadian rhythms, whose maintenance is particularly important for preventing recurrence of BD episodes. While a phase 4 study announced efficacy of ramelteon as maintenance therapy, 31 a phase 3 trial for its sublingual form, aiming at alternative ways of administration, was recently suspended due to financial reasons. Lurasidone Lurasidone is a new atypical antipsychotic that has been approved for the treatment of bipolar depression, either as monotherapy or as an add-on treatment. 32 Regarding relapse prevention, lurasidone is studied in three phase 3 trials (table 2), a double blind, one open-label as an add-on treatment and one open-label as monotherapy for 28, 12 and 52 weeks respectively. Results of these studies are expected. Asenapine Asenapine is an atypical antipsychotic for the treatment of schizophrenia and manic/mixed episode. Besides bipolar depression, 33 asenapine is studied as monotherapy in a double-blind trial, compared to placebo for mood episode prevention. Aripiprazole Aripiprazole is used as monotherapy or adjunctive treatment for manic/mixed episode and maintenance treatment, while it is controversial whether it is effective in bipolar depression For the time being, two phase 3 trials are investigating the use of

17 PSYCHIATRIKI 26 (3), 2015 PHARMACOLOGICAL AGENTS UNDER RESEARCH IN BIPOLAR DISORDER 175 long acting injectable aripiprazole for 52 weeks for BD maintenance therapy. Preclinical studies for maintenance therapy for bipolar disorder Our search for the last 5 years found 5 eligible studies corresponding to equal number of pharmacological agents (table 3), that showed efficacy in experimental models of both mania and depression. This inclusion criteria was considered more accurate, since there is no valid and reliable animal model of BD, due to difficulty to reflect the phenotype of switching symptoms of mania and depression at the same model. 37 CK01 The compound CK01 inhibits the function of the casein kinase 1 (CK1) ε/δ, which is believed to be involved in the modulation of the molecular clock and therefore circadian rythm. 38 CLOCK mice, carry a mutation in one of the essential proteins associated with maintaining circadian rhythm and present significant disruption of it along with a behavioral profile resembling a phenotype similar to human mania. In one study, CK01 was administered to CLOCK mice and then compared to lithium s action. Results showed reversal of anxiety-hyperactivity behavior (as lithium) and partial reversal of the phenotype of depression forcedswim test model. 39 The above results suggest that pharmaceutical agents that inhibit CK1, may have therapeutic value for BD. Ebselen Ebselen is a compound with significant antioxidant properties that inhibits monophosphatase inositol (IMP). It was observed that it mimics the action of lithium, probably because via the common neurobiological pathway of inositol recycling inhibition, exhibiting similar efficacy in preclinical stage. 40 It has been found to be effective in both depression 41 and Table 3. Preclinical trials for maintenance treatment in bipolar disorder. Compound Animal model Mania/Depression Mechanism of action Results Mania/Depression model CK01 CLOCK mice CK1 ε/δ inhibition Reversal of stress behavior - hyperactivity/partial reversal of depression phenotype Ebselen Peptide TAT KLCpCDK Cpd-60 Sodium butyrate (SB) Model: amphetamine-induced hyperactivity/forced swim test and tail suspension test in mice Model: amphetamine-induced hyperactivity/forced swim test and tail suspension test in mice Model: amphetamine-induced hyperactivity/forced swim test in mice Model: AMPH-induced hyperactivity in Wistar rats/maternal deprivation and chronic mild stress IMP inhibition GSK-3 inhibition of KLC2 phosphorylation and AMPA glutamate receptors modulation HDAC ½ inhibition HDAC inhibition Similar to the action of lithium: Reduction of the observed behavior of rearing and hyperactivity/reduction of immobility time Similar to the action of lithium: Reduction of the observed behavior of amphetamineinduced hyperactivity/reduction of immobility time Reduction of the observed behavior of amphetamineinduced hyperactivity/reduction of immobility time Reversal of mania/depression phenotype respectively CK: Casein kinase, IMP: Monophosphatase inositol, GSK-3: glycogen synthase kinase-3, KLC-2: kinase light chain 2, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, HDAC: Histone Deacetylase

18 176 S. DIMITRAKOPOULOS and G. KONSTANTAKOPOULOS PSYCHIATRIKI 26 (3), 2015 mania 40 models, and therefore a candidate agent for further study in treating BD. Peptide TAT KLCpCDK This peptide has been found to have lithium-like properties, inhibiting glycogen synthase-3 kinase (GSK-3), while additionally shows effectiveness in both models of depression and mania. 42 Although results of this study were announced in 2010, there have not been since then, known to us at least, further clinical trials for this agent in BD. Cpd-60 Cpd-60 acts as a selective 1/2 histone deacetylase (HDAC 1/2) inhibitor, modulating chromatin and gene expression in mouse brains. Evidence of its efficacy has been found in both mania and depression models. 43 Inhibition of HDAC may be a candidate target for the development of epigenetic acting agents that would have a therapeutic role in BD. Sodium Butyrate (SB) This compound, similarly to Cpd-60, inhibits HDAC and simultaneously exhibits neurotrophic activity. SB administration in experimental models of mania 44,45 and depression 44,46 resulted in amelioration of behavioral patterns, indicating a possible mood stabilizing role. Current limitations and prospects in maintenance treatment of BD The need to develop new treatments for BD is beyond any doubt. There are therapeutic difficulties in BD, especially in preventing depressive episodes or depressive residual symptoms or treating BD II in the long-term. 47 Lithium may be the golden option for relapse prevention, but, as noted above, a proportion of BD patients will not respond (nonresponders) 48 or be fully protected, regarding mixed or rapid-cycling type, and often will present side effects, 49 which impede therapeutic process. Moreover, many patients are treatment resistant, 50 presenting with residual symptoms during maintenance phase 51 and therefore ongoing treatment is considered inadequate. The phenomenon of polypharmacy 2 is also frequent in order to achieve stabilization and treat residual symptoms. Finally, new pharmaceutical agents which are developed based on the mechanism of lithium action or other pathophysiological pathways may contribute to the understanding of the underlying neurobiological substrates of BD. 52 From this review it appears that three active compounds (dextromethorphan, pregabalin, paliperidone) and possibly eslicarbazepine have shown some positive evidence for BD maintenance therapy. Considering, however, the methodology of these and other ongoing trials, there are marked differences in the definition of maintenance therapy, the required time for long-term prophylaxis and how efficacy of each intervention is evaluated. Measuring clinical levels of functioning or residual symptoms (mania or depression) does not seem to ensure longterm prevention. Regarding study design, it may be preferable to use days to relapse (for any major mood episode) or the number of individuals who will finally relapse as primary outcome measures and the longest, possible, follow-up time period for which a prophylactic treatment will be considered adequate. Methodological issues, such as diagnosis, clinical heterogeneity, gender differences and comorbidity, 53 should also be addressed in order to promote research. 52 Finally, regarding preclinical trials, there are important limitations in developing a reliable, valid BD model that will present both the pole of mania and depression in a single behavioral phenotype. 37 Based on the above concerning studies design, paliperidone seems to have favorable profile for further study as a mood stabilizer, although, for the moment, it seems to be effective only in the prevention of manic episodes. Cariprazine is another antipsychotic that presents with a novel mechanism of action and has shown good tolerability and safety. Results on the efficacy of cariprazine in maintenance treatment are expected, as well as from other atypical antipsychotics, namely lurasidone, asenapine and long-acting aripiprazole. Study results on the efficacy of NMDA receptors inhibitors, dextromethorphan and memantine, are so far mixed, although there is preliminary positive evidence for dextromethorphan. Pregabalin

19 PSYCHIATRIKI 26 (3), 2015 PHARMACOLOGICAL AGENTS UNDER RESEARCH IN BIPOLAR DISORDER 177 Η θεραπεία της διπολικής διαταραχής αποτελεί πρόκληση για τον σύγχρονο κλινικό και, παρά την πρόοδο της ψυχοφαρμακολογίας, οι επιλογές παραμένουν περιορισμένες και τα αποτελέσματα συχνά μη ικανοποιητικά. Η σύγχρονη έρευνα επικεντρώνεται στην ανεύρεση νέων φαρμακευτικών παραγόντων για όλες τις φάσεις της διπολικής διαταραχής, για την αντιμετώπιση μανιακών και καταθλιπτικών επεισοδίων και τη θεραπεία συντήρησης. Ιδιαίτερα η πρόληψη των υποτροπών και η μακροπρόθεσμη σταθεροποίηση συνιστά μείζονα θεραπευτικό στόχο. Οι συνδυαστικές θεραπείες και η πολυφαρμακία αποτελούν την πλέον συχνή τακτική επιλογή στη πρόληψη των υποτροπών. Επιπλέον, στη φάση συντήρησης οι ασθενείς βιώνουν συχνά υπολειπόμενα συμπτώματα από τη διάθεση, παρουσιάζουν γνωστικά ελλείμματα και λειτουργική έκπτωση, κάτι που καταδεικνύει τη μη επαρκή αποτελεσματικότητα των υπαρχουσών θεραπειών και την ανάγκη για νέες, στοχευμένες, αποτελεσματικές και ασφαλείς θεραπείες για τη διπολική διαταραχή. Η παρούσα ανασκόπηση εστιάζει σε δραστικές ουσίες για τη θεραπεία συντήρησης που διερευνώνται την τελευταία 5ετία. Οι υπό έρευνα ουσίες έχουν δοκιμαστεί ή δοκιμάζονται είτε ως μονοθεραπεία είτε ως θεραπεία ενίσχυσης σε κλινικές δοκιμές που έχουν προχωρήσει έως την φάση 3 ή σε προκλινικά μοντέλα διπολικής διαταραχής. Ενώ αναμένεται η ολοκλήρωση πολλών τρεχουσών μελετών, τα μέχρι τώρα αποτελέσματα δείχνουν ότι η παλιπεριδόνη και η πρεγκαμπαλίνη ίσως έχουν θέση στη θεραπεία συντήρησης της διπολικής διαταραχής. Επιπρόσθετα, η δεξτρομεθορφάνη, που δρα κυρίως ως NMDA ανταγωνιστής, παρουσιάζεται ως ενδιαφέρουσα ουσία για περαιτέρω μελέτη. Ωστόσο η μεμαντίνη που είναι επίσης NMDA ανταγωνιστής δεν έχει δώσει ενθαρρυντικά αποτελέσματα. Από την άλλη πλευρά, οι μέχρι τώρα δοκιμές ω-3 λιπαρά οξέα και κυτιδίνη δεν έδειξαν ανώτερη αποτελεσματικότητα σε σχέση με το εικονικό φάρμακο, παρόλο που έχουν τόσο νευροτροφικές όσο και νευροπροστατευτικές ιδιότητες. Η αντιεπιληand eslicarbazepine are anticonvulsants with prospects of further study in BD maintenance treatment. Trials of pharmaceutical agents with neuroprotective and/or neurotrophic properties, such as omega-3 fatty acids and cytidine, did not reveal positive results. Studies on the therapeutic benefit of modulating circadian rhythms in both experimental models and clinical trials, with CK01 and ramelteon respectively, have yielded encouraging results. In preclinical level, neurobiological pathways of GSK-3 and IMP inhibition, both related to the therapeutic effects of lithium, are known and important targets for the development of pharmaceutical agents for BD. 52,54 Pharmacological agents based on epigenetic changes and gene expression modulation, such as the inhibitor of HDAC, are earning more ground in modern research for BD. 52,54,55 Φαρμακολογικοί παράγοντες υπό μελέτη για τη θεραπεία συντήρησης στη διπολική διαταραχή Σ. Δημητρακόπουλος, 1 Γ. Κωνσταντακόπουλος 1,2 1 Α Ψυχιατρική Κλινική, Ιατρική Σχολή Πανεπιστημίου Αθηνών, Αιγινήτειο Νοσοκομείο, Αθήνα, 2 Section of Cognitive Neuropsychiatry, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King s College London, UK Ψυχιατρική 2015, 26:

20 178 S. DIMITRAKOPOULOS and G. KONSTANTAKOPOULOS PSYCHIATRIKI 26 (3), 2015 πτικής δράσης εσλικαρβαζεπίνη είχε κάποιες ενδείξεις αποτελεσματικότητας ως μονοθεραπεία. Όσον αφορά στις μελέτες σε προκλινικά, πειραματικά μοντέλα, οι υπό έρευνα ουσίες φαίνεται να ακολουθούν το νευροβιολογικό μονοπάτι του λιθίου, που εξακολουθεί να είναι η «χρυσή επιλογή» για την πρόληψη υποτροπών στη διπολική διαταραχή. Κύριοι θεραπευτικοί στόχοι είναι η συνθετική κινάση της γλυκόζης 3 (GSK-3) και το μονοπάτι της φωσφοϊνοσιτόλης (IMP), που υποστηρίζεται ότι εμπλέκονται στη δράση του λιθίου. Επιπλέον, η διατήρηση των κιρκάδιων ρυθμών εξετάζεται σε προκλινικές και κλινικές μελέτες με τη διερεύνηση της αποτελεσματικότητας και ασφάλειας των ουσιών CK-01 και ραμελτεόνης αντίστοιχα. Η έρευνα εστιάζει επίσης σε φαρμακευτικά μόρια που σχετίζονται με επιγεννητικές μεταβολές ή τη ρύθμιση της γονιδιακής έκφρασης, όπως η ιστόνη της δεακετυλάσης (HDAC). Θα πρέπει επίσης να επισημανθεί ότι η ανάπτυξη έγκυρων και αξιόπιστων πειραματικών μοντέλων διπολικής διαταραχής, που προς το παρόν παραμένει αρκετά αμφιλεγόμενη, θα συμβάλει στην κατανόηση των παθογενετικών μηχανισμών της αλλά και στην ανεύρεση κατάλληλων και αποτελεσματικών θεραπειών. Επίσης, η βελτίωση των μελετών σε μεθοδολογικά ζητήματα όπως η διάγνωση, η κλινική ετερογένεια, ο χρόνος παρακολούθησης, οι διαφορές ανάμεσα στα φύλα και η συννοσηρότητα, μπορεί να προαγάγουν την έρευνα. Οι τρέχουσες μελέτες αφήνουν περιθώρια για την ανάπτυξη νέων δραστικών ουσιών στο άμεσο μέλλον, μολονότι υπάρχουν μεθοδολογικοί περιορισμοί στην έρευνα για τη θεραπεία συντήρησης στη διπολική διαταραχή. Οι νέοι θεραπευτικοί στόχοι περιλαμβάνουν όχι μόνο τους ήδη γνωστούς μηχανισμούς δράσης αλλά και νέα παθοφυσιολογικά μονοπάτια που πιθανώς εμπλέκονται στη διπολική διαταραχή. Λέξεις ευρετηρίου: Διπολική διαταραχή, θεραπεία συντήρησης, νέοι θεραπευτικοί στόχοι, νέοι φαρμακολογικοί παράγοντες. References 1. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med 2005, 67: Bauer M, Glenn T, Alda M, Sagduyu K, Marsh W, Grof P et al. Drug treatment patterns in bipolar disorder: analysis of long-term self-reported data. Int J Bipolar Disord 2013, 1:5 3. Weinstock LM, Gaudiano BA, Epstein-Lubow G, Tezanos K, Celis-Dehoyos CE, Miller IW. Medication burden in bipolar disorder: a chart review of patients at psychiatric hospital admission. Psychiatry Res 2014, 216: Judd JL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002, 59: Burdick KE, Braga RJ, Goldberg JF, Malhotra Α. Cognitive dysfunction in bipolar disorder. CNS Drugs 2007, 21: MacQueen GM, Young LT, Joffe RT. A review of psychosocial outcome in patients with bipolar disorder. Acta Psychiatr Scand 2001, 103: Liu Y, Qin L, Li G, Zhang W, An L, Liu B et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 2003, 305: Mousavi SA, Saadatnia M, Khorvash F, Hoseini T, Sariaslani P. Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke. Arch Med Sci 2011, 7: Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Med Hypotheses 2011, 76: Chen SL, Lee SY, Chang YH, Chen PS, Lee IH, Wang TY et al. Τherapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder. Eur Neuropsychopharmacol 2014, 24: Schaffer LC, Schaffer CB, Miller AR, Manley JL, Piekut JA, Nordahl TE. An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder. J Affect Disord 2013, 147: Berwaerts, J. Melkote R, Nuamah I, Lim P. A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. J Affect Disord 2012, 138: Grunze H, Kotlik E, Costa R, Nunes T, Falcão A, Almeida L et al. Assessment of the efficacy and safety of eslicarbazepine acetate in acute mania and prevention of recurrence: Experience from multicentre, double-blind, randomised phase II clinical studies in patients with bipolar disorder I. J Affect Disord 2015, 174: Lu RB, Chen SL, Lee SY, Chang YH, Chen SH, Chu CH et al. Neuroprotective and neurogenesis agent for treating bipolar